Pharmaceutical compositions and the treatment of overactive bladder

ABSTRACT

The present invention relates to methods of treating overactive bladder and the symptoms associated therewith, for example, urinary urgency, frequency of micturitions, nocturia, and urgency urinary incontinence. One treatment method according to the present invention comprises treatment with the beta-3 adrenergic receptor agonist solabegron. Another treatment combination according to the invention comprises solabegron, and a muscarinic receptor antagonist which results in a synergistic effect on the symptoms associated with OAB.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Continuation of U.S. Ser. No. 15/868,582filed Jan. 11, 2018, now U.S. Pat. No. 10,350,182, which is aContinuation of U.S. Ser. No. 15/323,685 filed on Jan. 3, 2017, now U.S.Pat. No. 9,907,767, which is a Continuation-In-Part of InternationalApplication No. PCT/US2015/038583 filed Jun. 30, 2015, which claimspriority to U.S. Provisional Application No. 62/020,889 filed Jul. 3,2014; U.S. Ser. No. 15/323,685 is also a Continuation in Part of U.S.Ser. No. 15/235,720 filed Aug. 12, 2016, which is a Continuation of U.S.Ser. No. 13/762,563 filed on Feb. 8, 2013, now U.S. Pat. No. 9,522,129,which claims priority to U.S. Provisional Application Ser. No.61/596,893 filed on Feb. 9, 2012; U.S. Ser. No. 13/762,563 is also aContinuation-In-Part of U.S. Ser. No. 13/196,068 filed on Aug. 2, 2011,now U.S. Pat. No. 8,642,661, which claims priority to U.S. ProvisionalApplication Ser. No. 61/370,171 filed on Aug. 3, 2010. The disclosuresof the aforementioned are herein incorporated by reference in theirentirety.

SUMMARY OF THE INVENTION

Normally, the kidneys produce urine, which drains into the bladder.During urination, urine passes from the bladder through the urethra. Asthe bladder fills, nerve signals sent to the brain trigger the need tourinate and the nerve signals coordinate the relaxation of the pelvicfloor muscles and the muscles of the urethra (urinary sphinctermuscles). The muscles of the bladder contract, pushing the urine out(micturition). Overactive bladder occurs because the muscles of thebladder start to contract involuntarily even when the volume of urine inthe bladder is low. This involuntary contraction creates the urgent needto urinate.

Overactive bladder (OAB) is a condition characterized by sudden,involuntary contraction of the detrusor muscle of the urinary bladder.This results in a sudden, compelling need to urinate that is difficultto suppress (urinary urgency), even though the bladder may only containa small amount of urine. The key symptom is the sudden urge to void(urgency) with or without urgency urinary incontinence, often associatedwith urinary frequency (also known as frequency of micturitions, voiding8 or more times per day) and nocturia (awakening one or more times atnight to void). Overactive bladder coupled with urinary leakage(inability to suppress the urge to void) is also referred to as urgencyurinary incontinence. Approximately 300 mL of urine in the bladder cansignal the nerves to trigger muscles of the bladder to coordinateurination. Voluntary control of the sphincter muscles at the opening ofthe bladder can hold the urine in the bladder for longer. Up to 600 mLof urine can be contained in a normal adult bladder. For those with OAB,the bladder capacity is typically low (<200 mL).

OAB is commonly classified into subtypes including neurogenic,idiopathic, and outlet obstruction. Neurogenic OAB is attributed tocoexisting neurological conditions such as Parkinson's disease, multiplesclerosis, spinal cord injury, or stroke. The underlying pathophysiologyis the interruption of the otherwise orderly control of micturition,resulting in the symptoms described above. The cause of idiopathic OABis not as well defined; alterations in signaling within the bladder havebeen implicated. Finally, OAB may be associated with anatomical changesin the lower urinary tract, for example, in patients with bladder outletobstruction, which may be the result of an enlarged prostate gland.

Overall, the incidence of OAB increases with age. The ratio of men towomen affected depends on the age group, but in general women tend to bemore affected than men. OAB represents a significant quality of lifeburden to patients.

OAB treatment goals include: 1) reduction of urinary urgency andfrequency of micturitions, 2) increase in voided volume (bladdercapacity), 3) decrease in urge incontinence (reduction of leakageepisodes), and 4) decrease in nocturia. Physicians and patients remainunsatisfied with the current therapies and desire medicines withimproved efficacy and tolerability. In particular, there is anunacceptably high incidence of side effects, including dry mouth andconstipation associated with these medications. Also, currentmedications do not adequately treat urgency, one of the most bothersomesymptoms of OAB.

Accordingly, there remains a need for new medicines and methods oftreatment that offer improved efficacy and tolerability in the treatmentof symptoms associated with overactive bladder, above and beyond thecurrently available therapies.

The present invention provides pharmaceutical compositions andcombinations to treat OAB and the symptoms associated therewith withoutthe unacceptable side effects seen with the current treatment methods.One treatment method according to the present invention comprisestreatment with the beta-3 adrenergic receptor agonist solabegron.Another treatment combination according to the invention comprises abeta-3 adrenergic receptor agonist, e.g. solabegron, and a muscarinicreceptor antagonist which results in a synergistic effect on thesymptoms associated with OAB. The inventors have shown that thiscombination provides an unexpected increase in bladder capacity measuredas voided volume and is therefore useful for the treatment of one ormore symptoms associated with OAB. For example, a goal of OAB treatmentis to decrease micturition frequency. This is one of the recognizedendpoints for treatment of OAB. Accordingly, if voided volume increases,and intake remains the same, then the number of micturitions (i.e.micturition frequency) will decrease. This is a major goal of treatingOAB.

Accordingly, in one embodiment, the present application describes amethod of treating overactive bladder in a subject in need thereof,comprising administering a therapeutically effective amount ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof, whereintreating overactive bladder is measured by an increase in voided volume.

In one embodiment the present application describes a method of treatingoveractive bladder in a subject in need thereof, comprisingadministering a therapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, wherein the voided volume of thesubject is increased.

In one embodiment the present application describes a method of treatingoveractive bladder in a subject in need thereof, comprisingadministering a combination comprising a therapeutically effectiveamount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof, and anantimuscarinic receptor agonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof, wherein treatingoveractive bladder is measured by an increase in voided volume.

In one embodiment the present application describes a method of treatingoveractive bladder in a subject in need thereof, comprisingadministering a combination comprising a therapeutically effectiveamount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof, and anantimuscarinic receptor agonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof, wherein the voidedvolume of the subject is increased.

In one embodiment the present application describes a pharmaceuticalcomposition for treating overactive bladder, comprising solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, wherein treating overactive bladderis measured by an increase in voided volume.

In one embodiment the present application describes a pharmaceuticalcombination for treating overactive bladder comprising, atherapeutically effective amount of solabegron andpharmaceutically-acceptable salts thereof; and a therapeuticallyeffective amount, or a sub-therapeutically effective amount oftolterodine or a pharmaceutically-acceptable salt thereof, whereintreating overactive bladder is measured by an increase in voided volume.

In one embodiment the present application describes a pharmaceuticalcombination for treating overactive bladder comprising, atherapeutically effective amount of solabegron andpharmaceutically-acceptable salts thereof; and a therapeuticallyeffective amount, or a sub-therapeutically effective amount ofoxybutynin or a pharmaceutically-acceptable salt thereof, whereintreating overactive bladder is measured by an increase in voided volume.

In one embodiment the present application describes a pharmaceuticalcombination for treating overactive bladder comprising, atherapeutically effective amount of solabegron andpharmaceutically-acceptable salts thereof; and a therapeuticallyeffective amount, or a sub-therapeutically effective amount ofsolifenacin or a pharmaceutically-acceptable salt thereof, whereintreating overactive bladder is measured by an increase in voided volume.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of the Experimental protocol described in Example3.

FIG. 2 displays the effects of antimuscarinics on CL-316,243 inhibitionof EFS-induced contractions of rat isolated urinary bladder.

FIG. 3 displays the effects of various antimuscarinics on solabegroninhibition of EFS-induced contractions of rat isolated urinary bladder.

FIG. 4 displays the effects of various antimuscarinics on mirabegroninhibition of EFS-induced contractions of rat isolated urinary bladder.

FIG. 5 shows E_(max) and pIC₅₀ values of various beta-3 adrenergeicreceptor agonists, either alone (vehicle) or in the presence of 10 nM ofvarious antimuscarinics.

DETAILED DESCRIPTION OF THE INVENTION Definitions

This invention is not limited to the particular processes, compositions,or methodologies described, as these may vary. The terminology used inthe description is for the purpose of describing the particular versionsor embodiments only, and is not intended to limit the scope of thepresent invention. Unless defined otherwise, all technical andscientific terms used herein have the same meanings as commonlyunderstood by one of ordinary skill in the art. All publicationsmentioned herein are incorporated by reference in their entirety.Nothing herein is to be construed as an admission that the invention isnot entitled to antedate such disclosure by virtue of prior invention.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “symptom” is a reference to one or more symptoms and equivalentsthereof known to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50 mL means in the range of 45 mL-55 mL.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a patient whereby the therapeutic positivelyimpacts the tissue to which it is targeted. “Administering” acomposition may be accomplished orally, by injection, topicaladministration, or by either method in combination with other knowntechniques. Such combination techniques include heating, radiation andultrasound.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals.

The term “improves” is used to convey that the present invention changeseither the appearance, form, characteristics and/or the physicalattributes of the tissue to which it is being provided, applied oradministered.

The term “inhibiting” includes the administration of a compound of thepresent invention to prevent the onset of the symptoms, alleviating thesymptoms, reducing the symptoms, delaying or decreasing the progressionof the disease and/or its symptoms, or eliminating the disease,condition or disorder.

By “pharmaceutically-acceptable” it is meant that the carrier, diluentor excipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutically-acceptable derivative,” as used herein,refers to pharmaceutically-acceptable solvates,pharmaceutically-acceptable salts solvated withpharmaceutically-acceptable solvents thereof, and metabolites.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent, or improve an unwanted condition or diseaseof a patient. In part, embodiments of the present invention are directedto the treatment of overactive bladder.

As used herein, the term “effective amount” means the amount of a drugor pharmaceutical agent, or the amount of a combination of drugs orpharmaceutical agents that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder, as was known in the art as of the date of thepresent invention. The term also includes within its scope amountseffective to enhance normal physiological function, as was known in theart as of the date of the present invention.

Accordingly, the term “sub-therapeutically effective amount” indicatesany amount of the muscarinic receptor antagonist which is nottherapeutically effective or is minimally therapeutically effectivealone, as was known in the art as of the date of the present invention,but which in combination with a therapeutically effective amount of thebeta-3 adrenergic receptor agonist, e.g. solabegron, demonstrates asynergistic therapeutic effect. In particular embodiments of thepresently claimed combinations and methods, a lower dose(sub-therapeutic dose) of the antimuscarinic agent can be used toproduce superior efficacy of the combination due to the synergy of thetwo compounds, while avoiding or minimizing the side effects of theantimuscarinic agent.

The terms “treat,” “treated,” or “treating” as used herein refers toboth therapeutic treatment and prophylactic or preventative measures,wherein the object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder or disease, or to obtain beneficial ordesired clinical results. For the purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment.

In some embodiments, the compounds and methods disclosed herein can beutilized with or on a subject in need of such treatment, which can alsobe referred to as “in need thereof.” As used herein, the phrase “in needthereof” means that the subject has been identified as having a need forthe particular method or treatment and that the treatment has been givento the subject for that particular purpose.

Generally speaking, the term “tissue” refers to any aggregation ofsimilarly specialized cells which are united in the performance of aparticular function.

As used herein, the terms “synergy” and “synergistic”, or the phrase “ina synergistic manner,” refer to the interaction of two or more drugs invitro or in vivo so that their combined effect when administeredtogether is greater than the sum of the effects observed when each isadministered individually.

As used herein, the term “urinary urgency” is considered the hallmarksymptom of OAB, and is the sudden, compelling desire to pass urine thatis difficult to defer.

As used herein, the term “urinary frequency” or “frequency ofmicturitions” refers to the number of times a subject voids and isconsidered abnormal if the person urinates more than eight times in aday. This frequency is usually monitored by having the person recordurination episodes in a voiding diary. The number of episodes variesdepending on sleep, fluid intake, medications, and up to seven isconsidered normal if consistent with the other factors.

The term “nocturia,” as used herein, is a symptom where the personcomplains of interrupted sleep because of an urge to void and, similarto the urinary frequency component, is affected by similar lifestyle andmedical factors. Individual waking events are not considered abnormal.

As used herein, the term “urgency urinary incontinence” is a form ofurinary incontinence characterized by the involuntary loss of urineoccurring for no apparent reason while feeling urinary urgency asdiscussed above. Urgency urinary incontinence can be measured with padtests, and these are often used for research purposes. The goal intreating urgency urinary incontinence is to reduce the number of leakageepisodes.

As used herein, the term “voided volume” is used as a measure of bladdercapacity. Anatomically, functional bladder capacity increases with agefrom childhood [(years of age+2)×30 mL] to adulthood (300-600 mL). Agoal when treating OAB is to increase the bladder capacity or voidedvolume. An increase in voided volume is a good indicator of the efficacyof a therapy. For example, a goal of OAB treatment is to decreasemicturition frequency. This is one of the recognized endpoints fortreatment of OAB. Accordingly, if voided volume increases, and intakeremains the same, then the number of micturitions (i.e. micturitionfrequency) will decrease.

As used herein, the terms “muscarinic receptor antagonists,”“antimuscarinics”, “antimuscarinic agent” and “anticholinergics” aresynonymous.

The embodiments set forth herein are described in terms of “comprising”,however each of the following embodiments may also be described in termsof “consists of” or “consisting of”, meaning that the formulation ormethod includes only the elements, steps, or ingredients specificallyrecited in the particular claimed embodiment or claim and each of theembodiments may also be described in terms of “consisting essentiallyof” or “consists essentially of”, meaning that the formulation or methodincludes only the specified materials or steps and those that do notmaterially affect the basic and novel characteristics of the claimedinvention.

Methods of Treatment

Solabegron

The adult urinary bladder has a total volume capacity range between 300and 600 mL. A component of bladder capacity is the post-void residual(PVR) urine test, which measures the amount of urine left in the bladderafter voluntary bladder emptying (urination). The volume of urine voidedor voided volume (functional capacity) plus the PVR volume equals thetotal bladder capacity.

Total bladder capacity (volume) is also measured clinically in an awakepatient by transabdominal ultrasound when the bladder is filled tocompletion. Total bladder capacity (volume) is calculated by measuringthe voided volume by the patient, and then measuring the post-voidresidual volume by either transabdominal ultrasound or directmeasurement by bladder catheterization. Residual urine is defined as theamount left post-voiding and the voided volume is the amount of volumepassed during a micturition. Thus, the total bladder capacity (bladdervolume) is equal to the voided volume (functional bladder capacity) plusthe PVR volume.

Various embodiments of the present invention describe treatingoveractive bladder in a subject in need thereof, wherein treatingoveractive bladder is measured by an increase in voided volume.

In some embodiments, the method comprises administering atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof. Solabegron is also known as3′-[(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino]biphenyl-3-carboxylicacid and is depicted in Formula I:

In some embodiments, the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof,comprises one or more pharmaceutically-acceptable carriers, diluents orexcipients.

In some embodiments, solabegron is in the form of the hydrochloride salt(Formula I-HCl). In some embodiments, solabegron is a zwitterion(Formula I-ZW).

In some embodiments the method of treatment is directed to a methodcomprising the solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof, furthercomprising the primary in vivo metabolite of solabegron, Formula (III)

In certain embodiments, the therapeutically effective amount ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof, may be asa daily dose or a single dose within a range of a lower limit ofsolabegron and an upper limit amount of solabegron. In some embodimentsthe lower limit amount of solabegron is about 25 mg, about 50 mg, about75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325mg, about 350 mg, about, 375 mg, about 400 mg, about 425 mg, about 450mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700mg, about 725 mg, or about 750 mg. In some embodiments, the upper limitamount of solabegron is about 775 mg, about 750 mg, about 725 mg, about700 mg, about 675 mg, about 650 mg, about 625 mg, about 600 mg, about575 mg, about 550 mg, about 525 mg, about 500 mg, about 475 mg, about450 mg, about 425 mg, about 400 mg, about 375 mg, about 350 mg, about325 mg, about 300 mg, about 275 mg, about 250 mg, about 225 mg, about200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75mg, or about 50 mg. In some embodiments, the daily dose may be any rangebetween an upper and a lower limit of ranges previously disclosed.

For example, the daily dose range may be about 25 mg to about 775 mg,about 50 mg to about 500 mg, about 100 mg to about 750 mg, about 150 mgto about 700 mg, about 200 mg to about 400 mg, about 200 mg to about 650mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg, about350 mg to about 500 mg, about 400 mg to about 450 mg of solabegron. Insome embodiments the daily dose is administered twice daily (i.e. a 25mg to 775 mg daily dose is administered as two doses of 12.5 mg to 387.5mg).

In certain embodiments the therapeutically effective amount ofsolabegron is 50 mg to 500 mg a day given in an immediate releaseformulation. In certain embodiments the therapeutically effective amountof solabegron is 25 mg to 250 mg, given twice a day in an immediaterelease formulation. In certain embodiments the therapeuticallyeffective amount is 100 mg to 200 mg, given twice a day in an immediaterelease formulation.

In certain embodiments the method further comprises, alleviating one ormore of the symptoms of overactive bladder selected from the groupconsisting of urinary urgency, frequency of micturitions, nocturia, andurgency urinary incontinence, or a combination thereof.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof; wherein treating overactive bladder is measuredby an increase in voided volume; and wherein the solabegron is in apharmaceutical composition comprising one or morepharmaceutically-acceptable carriers, diluents, or excipients.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of a hydrochloride salt of solabegron,wherein treating overactive bladder is measured by an increase in voidedvolume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of a zwitterion of solabegron, whereintreating overactive bladder is measured by an increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof; wherein treating overactive bladder is measuredby an increase in voided volume; and wherein the therapeuticallyeffective amount of solabegron is about 25 mg to about 775 mg. Incertain embodiments the therapeutically effective amount of solabegronis about 50 mg to about 500 mg, about 100 mg to about 750 mg, about 150mg to about 700 mg, about 200 mg to about 400 mg, about 200 mg to about650 mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg,about 350 mg to about 500 mg, about 400 mg to about 450 mg. Thesedosages may be administered once a day, twice daily, three times a day,or four times a day. In some embodiments the daily dose is administeredtwice daily (i.e. a 25 mg to 775 mg daily dose is administered as twodoses of 12.5 mg to 387.5 mg). In certain embodiments thetherapeutically effective amount of solabegron is 50 mg to 500 mg a daygiven in an immediate release formulation. In certain embodiments thetherapeutically effective amount of solabegron is 25 mg to 250 mg, giventwice a day in an immediate release formulation. In certain embodimentsthe therapeutically effective amount is 100 mg to 200 mg, given twice aday in an immediate release formulation.

In embodiments described herein, a method of treating overactive bladderin a subject in need thereof, comprises administering a therapeuticallyeffective amount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof; whereintreating overactive bladder is measured by an increase in voided volumeand one or more of the symptoms of overactive bladder is alleviated;wherein the one or more symptoms of overactive bladder is selected fromthe group consisting of urinary urgency, frequency of micturitions,nocturia, and urgency urinary incontinence, or a combination thereof.

In certain embodiments, a method of treating overactive bladder in asubject in need thereof, comprises administering a therapeuticallyeffective amount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; whereinthe voided volume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof; wherein the voided volume of the subject isincreased; and wherein the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative, or zwitterion thereof, isin a pharmaceutical composition comprising one or morepharmaceutically-acceptable carriers, diluents, or excipients.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of a hydrochloride salt of solabegron,wherein the voided volume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of a zwitterion of solabegron, whereinthe voided volume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, wherein the voided volume of the subject isincreased and, wherein the therapeutically effective amount ofsolabegron is about 25 mg to about 775 mg. In certain embodiments thetherapeutically effective amount of solabegron is about 50 mg to about500 mg, about 100 mg to about 750 mg, about 150 mg to about 700 mg,about 200 mg to about 400 mg, about 200 mg to about 650 mg, about 250 mgto about 600 mg, about 300 mg to about 550 mg, about 350 mg to about 500mg, about 400 mg to about 450 mg. These dosages may be administered oncea day, twice daily, three times a day, or four times a day. In someembodiments the daily dose is administered twice daily (i.e. a 25 mg to775 mg daily dose is administered as two doses of 12.5 mg to 387.5 mg).In certain embodiments the therapeutically effective amount ofsolabegron is 50 mg to 500 mg a day given in an immediate releaseformulation. In certain embodiments the therapeutically effective amountof solabegron is 25 mg to 250 mg, given twice a day in an immediaterelease formulation. In certain embodiments the therapeuticallyeffective amount is 100 mg to 200 mg, given twice a day in an immediaterelease formulation. In embodiments described herein, the method oftreating overactive bladder in a subject in need thereof, comprisesadministering a therapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, wherein the voided volume of thesubject is increased, and one or more of the symptoms of overactivebladder is alleviated, wherein the one or more symptoms of overactivebladder is selected from the group consisting of urinary urgency,frequency of micturitions, nocturia, and urgency urinary incontinence,or a combination thereof.

Solabegron and a Muscarinic Receptor Antagonist

Unexpectedly, new synergistic drug combinations have also beendiscovered which are useful in treating one or more symptoms associatedwith OAB. These combinations comprise solabegron, and a muscarinicreceptor antagonist. It has been demonstrated that these combinationshave surprisingly increased potency and efficacy, and are useful for thetreatment of at least one symptom associated with OAB.

Treating patients with the combination of solabegron and anantimuscarinic agent has now been found to synergistically increasevoided volume, thereby increasing total bladder capacity. Thecombination of solabegron and an antimuscarinic agent, two distinctpharmacological agents modulating independent bladder signalingpathways, produces synergistic increases in bladder capacity, whichcorrelates with clinical improvement.

The bladder receives motor innervation from both sympathetic andparasympathetic nerve fibers. Bladder function is the product of thecoordination of two different components of smooth muscles in thebladder, including the detrusor muscle. One component involvesparasympathetic nerves responsible for contraction of smooth bladdermuscles as the volume of urine stretches the bladder, and the otherinvolves sympathetic nerves that maintain the smooth bladder muscles ina relaxed state despite the stretching of the bladder.

Muscarinic receptor antagonists act via blockade of parasympatheticnerve mediated bladder contraction, while beta-3 adrenergic receptoragonists, e.g. solabegron, exert their effect by binding to beta-3adrenergic receptors, resulting in relaxation of sympathetic nervemediated smooth bladder muscle.

Testing of combination of solabegron and a muscarinic receptorantagonist according to the present invention produced a unexpectedsynergistic increase in voided volume compared to either solabegron orthe muscarinic receptor antagonist used alone and is therefore usefulfor the treatment of one or more symptoms associated with OAB (videsupra).

There was no reason to expect the two neural networks to functioncomplementarily in the bladder, so that blocking muscarinic receptorsand activating beta-3 adrenergic receptors would produce even acompletely additive increase in bladder capacity and voided volumecompared to individual results obtained, let alone a synergisticincrease. It was possible that relaxing the bladder muscle providedlittle further contribution to bladder capacity than already obtained byblocking bladder muscle contraction or vice versa. Accordingly, it wascompletely unexpected that a synergistic, i.e., more than additive,increase in bladder capacity was obtained by the combination products ofthe present invention compared to either component used alone when therewas no expectation that simultaneous blocking of parasympathetic nervefunction and activation of sympathetic function would produce even afully additive effect.

Muscarinic receptors responding to the natural ligand acetylcholine(ACh) have a widespread tissue distribution and are involved in thecontrol of numerous central and peripheral physiological responses, aswell as being a major drug target in human disease. This family ofG-protein coupled receptors consists of five members designated M1, M2,M3, M4 and M5. The gene family as a whole shows 26.3% overall amino acididentity, with the variation between the receptor subtypes being seenlargely within the intracellular loops. These receptors are sub-dividedinto two broad groups based on their primary coupling efficiency toG-proteins. Hence, M2 and M4-muscarinic receptors are able to couple tothe pertussis-toxin sensitive Gl/o-proteins, and M1, M3 andM5-muscarinic receptors couple to Gq/11-proteins. It is, however,readily apparent that the muscarinic receptor family can couple to awide range of diverse signaling pathways, some of which are mediated byG-proteins and others that are G-protein-independent.

The role of muscarinic receptors in the direct contraction of smoothmuscle, particularly of bladder, ileum, iris and airways, are considereda classical muscarinic response mediated principally by M3-muscarinicreceptors expressed on the smooth muscle cells. Co-expressed with theM3-muscarinic receptors in smooth muscle is an often-larger populationof M2-muscarinic receptors that appear to play a much lesser role in thesmooth muscle contractile response. Exocrine secretion, particularly ofsaliva, is primarily mediated by M3-muscarinic receptors with a lesserrole played by M1-receptors particularly in salvation.

The orthosteric binding pocket of the muscarinic receptor family ishighly conserved. (Leach, K., et al., Handb Exp Pharmacol. 208:29-48,2012). Currently, oxybutynin, tolterodine, solifenacin are the leadingantimuscarinic drugs that are employed for the treatment of overactivebladder. Tolterodine does not discriminate between the five subtypes.Oxybutynin and solifenacin possess very marginal selectivity (˜10-fold)for M₃ over the M₂/M₅ subtypes, but do not distinguish between M₃ andM₁/M₄ subtypes

Although not wishing to be bound by any particular theory, it isbelieved that beta-3 adrenergic receptor agonist, e.g. solabegron, exertan effect by binding to beta-3 adrenergic receptors, resulting inrelaxation of bladder smooth muscle. It is believed that muscarinicreceptor antagonists, such as oxybutynin, act via blockade ofparasympathetic nerve mediated bladder contraction. That drugs affectingthese two different mechanisms of action provide a synergistic effectthat was heretofore both unknown and unexpected.

Accordingly, in some embodiments, the present application describes amethod of treating overactive bladder in a subject in need thereof,comprising administering a combination comprising a therapeuticallyeffective amount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof, and atherapeutically or sub-therapeutically effective amount of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof, wherein treatingoveractive bladder is measured by an increase in voided volume.

In some embodiments the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof, isin a pharmaceutical composition comprising one or morepharmaceutically-acceptable carriers, diluents or excipients.

In some embodiments the muscarinic receptor antagonist or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof is in a pharmaceutical composition comprising one ormore pharmaceutically-acceptable carriers, diluents, or excipients.

In some embodiments, solabegron is in the form of the hydrochloride salt(Formula I-HCl). In some embodiments, solabegron is a zwitterion(Formula I-ZW).

In some embodiments, the muscarinic receptor antagonist is selected fromoxybutynin, tolterodine, trospium, darifenacin, festerodine,hyoscyamine, propiverine, or solifenacin, or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof. In some embodiments the muscarinic receptorantagonist is selected from oxybutynin, tolterodine, or solifenacin, ora pharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof. In some embodiments, muscarinic receptor antagonistis oxybutynin, or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof.

Oxybutynin (Formula (II)) has the chemical name 4-diethylaminobut-2-ynyl2-cyclohexyl-2-hydroxy-2-phenyl-ethanoate also known as4-(diethylamino)-2-butynyl-α-cyclohexyl-α-hydroxybenzeneacetate, alsoknown as4-(diethylamino)-2-butyn-1-yl-cyclo-hexyl-(hydroxy)phenylacetate, andmay be prepared, for example, according to the procedures provided in UKPatent Specification No. GB940,540, filed Jul. 25, 1961, and publishedon Oct. 30, 1963. The (S) enantiomer of oxybutynin may be preparedaccording to the procedures in EP 0806948 B1. The (R)-enantiomer ofoxybutynin may be prepared according to the procedures in U.S. Pat. No.6,123,961. Oxybutynin has been proven to be safe and effective intreating patients with overactive bladder and is marketed globally,although side effects are known.

In certain embodiments, the therapeutically effective amount ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof, may be asa daily dose or a single dose within a range of a lower limit ofsolabegron and an upper limit amount of solabegron. In some embodimentsthe lower limit amount of solabegron is about 25 mg, about 50 mg, about75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325mg, about 350 mg, about, 375 mg, about 400 mg, about 425 mg, about 450mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700mg, about 725 mg, or about 750 mg. In some embodiments, the upper limitamount of solabegron is about 775 mg, about 750 mg, about 725 mg, about700 mg, about 675 mg, about 650 mg, about 625 mg, about 600 mg, about575 mg, about 550 mg, about 525 mg, about 500 mg, about 475 mg, about450 mg, about 425 mg, about 400 mg, about 375 mg, about 350 mg, about325 mg, about 300 mg, about 275 mg, about 250 mg, about 225 mg, about200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75mg, or about 50 mg. In some embodiments, the daily dose may be any rangebetween an upper and a lower limit of ranges previously disclosed.

For example, the daily dose range may be about 25 mg to about 775 mg,about 25 mg to about 500 mg, about 100 mg to about 750 mg, about 150 mgto about 700 mg, about 200 mg to about 400 mg, about 200 mg to about 650mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg, about350 mg to about 500 mg, about 400 mg to about 450 mg of solabegron. Insome embodiments the daily dose is administered twice daily (i.e. a 25mg to 775 mg daily dose is administered as two doses of 12.5 mg to 387.5mg).

In certain embodiments the therapeutically effective amount ofsolabegron is 25 mg to 500 mg a day given in an immediate releaseformulation. In certain embodiments the therapeutically effective amountof solabegron is 12.5 mg to 250 mg, given twice a day in an immediaterelease formulation.

In certain embodiments, the therapeutically effective amount of themuscarinic receptor antagonist is the therapeutically effective amount,as was known in the art as of the date of the present invention.

In one embodiment, a therapeutically effective amount of oxybutynin is,but is not limited to, about 5 mg to about 30 mg daily. In someembodiments, the therapeutically effective amount of oxybutynin is 5 mgtwo to four times a day in an immediate release formulation. In certainembodiments, the therapeutically effective amount of oxybutynin is about5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mgonce a day in an extended release formulation.

In one embodiment, a therapeutically effective amount of tolterodine is,but is not limited to, about 1 mg to about 4 mg daily. In someembodiments, the therapeutically effective amount of tolterodine isabout 1 mg to about 2 mg two times a day in an immediate releaseformulation. In some embodiments, the therapeutically effective amountof tolterodine is about 2 mg to about 4 mg once a day in an extendedrelease formulation.

In one embodiment, a therapeutically effective amount of trospium is,but is not limited to, about 20 mg to about 60 mg daily. In someembodiments, the therapeutically effective amount of trospium is about20 mg two times a day in an immediate release formulation. In someembodiments, the therapeutically effective amount of trospium is about60 mg once a day in an extended release formulation.

In one embodiment, a therapeutically effective amount of darifenacin is,but is not limited to, about 7.5 mg to about 15 mg daily. In someembodiments, the therapeutically effective amount of darifenacin isabout 7.5 mg to about 15 mg once a day

In one embodiment, a therapeutically effective amount of festerodine is,but is not limited to, about 4 mg to about 8 mg daily. In someembodiments, the therapeutically effective amount of festerodine is 4 mgto 8 mg once a day.

In one embodiment, a therapeutically effective amount of hyoscyamine is,but is not limited to, about 0.375 mg to about 0.75 mg daily.

In one embodiment, a therapeutically effective amount of propiverine is,but is not limited to, about 15 mg to about 45 mg daily of propiverinehydrochloride. In some embodiments, the therapeutically effective amountof propiverine is about 15 mg two to three times a day of propiverinehydrochloride.

In one embodiment, a therapeutically effective amount of solifenacin is,but is not limited to, about 5 mg to about 10 mg daily. In someembodiments, the therapeutically effective amount of solifenacin isabout 5 mg or about 10 mg once a day.

In certain embodiments, the therapeutically effective amount of themuscarinic receptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof, may be as a daily doseor a single dose within a range of a lower limit of muscarinic receptorantagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof, and an upper limitamount of muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof. In some embodiments the lower limit amount of themuscarinic receptor antagonist is about 0.3 mg, about 0.75 mg, about 1mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,or about 85 mg. In some embodiments, the upper limit amount of themuscarinic receptor antagonist is about 90 mg, about 85 mg, about 80 mg,about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg,about 20 mg, about 15 mg, about 10 mg, about 5 mg, about 1 mg, or about0.75 mg. In some embodiments, the daily dose may be any range between anupper and a lower limit of ranges previously disclosed.

For example, the range may be about 0.375 mg to about 0.75 mg, about 1mg to about 4 mg, about 4 mg to about 8 mg, about 5 mg to about 10 mg,about 5 mg to about 30 mg, about 5 mg to about 85 mg, about 10 mg toabout 80 mg, about 15 mg to about 45 mg, about 15 mg to about 75 mg,about 20 mg to about 60 mg, about 20 mg to about 70 mg, about 25 mg toabout 65 mg, about 30 mg to about 60 mg, about 35 mg to about 55 mg,about 40 mg to about 50 mg of muscarinic receptor. These dosages may beadministered once a day, twice daily, three times a day, or four times aday.

In certain embodiments the sub-therapeutically effective of themuscarinic receptor antagonist is any amount of the muscarinic receptorantagonist which is not therapeutically effective or is minimallytherapeutically effective alone, as was known in the art as of the dateof the present invention, but which in combination with atherapeutically effective amount of solabegron, demonstrates asynergistic therapeutic effect.

In some embodiments of the invention, the sub-therapeutically effectiveamount of the muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, may be as a daily dose or a single dose within arange of a lower limit of the sub-therapeutically effective amount ofmuscarinic receptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof and an upper limit amountof the sub-therapeutically effective amount of muscarinic receptorantagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof. In some embodiments thelower limit amount of the sub-therapeutically effective amount of themuscarinic receptor antagonist is about 0.1 mg, about 0.5 mg, about 1mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, or about 45 mg. In someembodiments, the upper limit amount of the sub-therapeutically effectiveamount of the muscarinic receptor antagonist is about 50 mg, about 45mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg,about 15 mg, about 10 mg, about 5 mg, or about 1 mg. In someembodiments, the daily dose may be any range between an upper and alower limit of ranges previously disclosed.

For example, the range may be about 0.1 mg to about 50 mg, about 1 mg toabout 45 mg, about 5 mg to about 40 mg, about 10 mg to about 35 mg,about 15 mg to about 30 mg, about 20 mg to about 25 mg, of thesub-therapeutically effective amount of muscarinic receptor antagonist.These dosages may be administered once a day, twice daily, three times aday, or four times a day.

In certain embodiments, the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof, andthe muscarinic receptor antagonist or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof. areco-administered. In some embodiments the solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, and the muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, are contained in a single dosage form, wherein thesingle dosage form is a pharmaceutical composition.

In certain embodiments the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof, andthe muscarinic receptor antagonist or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof, areadministered separately.

In some embodiments there is a time delay between the administration ofthe solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof and themuscarinic receptor antagonist or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof. In someembodiments, the time delay between the administration of solabegron ora pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof, and the muscarinic receptor antagonistor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof, is 5 minutes, 10 minutes, 15 minutes,20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes,50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.

In some embodiments, the method further comprises alleviating one ormore of the symptoms of overactive bladder selected from the groupconsisting of urinary urgency, frequency of micturitions, nocturia, andurgency urinary incontinence, or a combination thereof.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, and one or morepharmaceutically-acceptable carriers, diluents, or excipients; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof; wherein treating overactive bladder is measured byan increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof, and one or morepharmaceutically-acceptable carriers, diluents, or excipients; whereintreating overactive bladder is measured by an increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof, selected from a groupconsisting of oxybutynin, tolterodine, and solifenacin; wherein treatingoveractive bladder is measured by an increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of oxybutynin or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof; wherein treating overactive bladder is measured byan increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of ahydrochloride salt of solabegron; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of azwitterion of solabegron; and a therapeutically effective amount, or asub-therapeutically effective amount, of a muscarinic receptorantagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof, and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume; andwherein the therapeutically effective amount of solabegron is about 25mg to about 775 mg. In certain embodiments, the therapeuticallyeffective amount of solabegron is about 25 mg to about 500 mg, about 100mg to about 750 mg, about 150 mg to about 700 mg, about 200 mg to about400 mg, about 200 mg to about 650 mg, about 250 mg to about 600 mg,about 300 mg to about 550 mg, about 350 mg to about 500 mg, about 400 mgto about 450 mg. These dosages may be administered once a day, twicedaily, three times a day, or four times a day. In some embodiments thedaily dose is administered twice daily (i.e. a 25 mg to 775 mg dailydose is administered as two doses of 12.5 mg to 387.5 mg). In certainembodiments the therapeutically effective amount of solabegron is 25 mgto 500 mg a day given in an immediate release formulation. In certainembodiments the therapeutically effective amount of solabegron is 12.5mg to 250 mg, given twice a day in an immediate release formulation.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof, and a therapeutically effective amountof a muscarinic receptor antagonist or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof; whereintreating overactive bladder is measured by an increase in voided volume;and wherein the therapeutically effective amount of muscarinic receptorantagonist is about 0.3 mg to about 90 mg. In certain embodiments, thetherapeutically effective amount of the muscarinic receptor antagonistis about 0.375 mg to about 0.75 mg, about 1 mg to about 4 mg, about 4 mgto about 8 mg, about 5 mg to about 10 mg, about 5 mg to about 30 mg,about 5 mg to about 85 mg, about 10 mg to about 80 mg, about 15 mg toabout 45 mg, about 15 mg to about 75 mg, about 20 mg to about 60 mg,about 20 mg to about 70 mg, about 25 mg to about 65 mg, about 30 mg toabout 60 mg, about 35 mg to about 55 mg, about 40 mg to about 50 mg.These dosages may be administered once a day, twice daily, three times aday, or four times a day.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof; wherein treating overactive bladder is measured byan increase in voided volume, and wherein the sub-therapeuticallyeffective amount of muscarinic receptor antagonist is any amount of themuscarinic receptor antagonist which is not therapeutically effective oris minimally therapeutically effective alone, as was known in the art asof the date of the present invention, but which in combination with atherapeutically effective amount of solabegron, demonstrates asynergistic therapeutic effect.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume, andwherein the solabegron and the muscarinic receptor antagonist areco-administered.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume, andwherein the solabegron and the muscarinic receptor antagonist arecontained in a single dosage form, wherein the single dosage form is apharmaceutical composition.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume, andwherein the solabegron and the muscarinic receptor antagonist areadministered separately.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume, andwherein there is a time delay between the administration of thesolabegron and the muscarinic receptor antagonist.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume and oneor more of the symptoms of overactive bladder is alleviated; wherein theone or more symptoms of overactive bladder is selected from the groupconsisting of urinary urgency, frequency of micturitions, nocturia, andurgency urinary incontinence, or a combination thereof.

In certain embodiments, a method of treating overactive bladder in asubject in need thereof, comprises administering a combinationcomprising a therapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and one or morepharmaceutically-acceptable carriers, diluents, or excipients; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof; wherein the voided volume of the subject isincreased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; and one or morepharmaceutically-acceptable carriers, diluents, or excipients; whereinthe voided volume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; selected from a groupconsisting of oxybutynin, tolterodine, and solifenacin; wherein thevoided volume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of oxybutynin or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, wherein the voided volume of the subject isincreased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of ahydrochloride salt of solabegron; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of azwitterion of solabegron; and a therapeutically effective amount, or asub-therapeutically effective amount, of a muscarinic receptorantagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein the therapeuticallyeffective amount of solabegron is about 25 mg to about 775 mg. Incertain embodiments, the therapeutically effective amount of solabegronis about 25 mg to about 500 mg, about 100 mg to about 750 mg, about 150mg to about 700 mg, about 200 mg to about 400 mg, about 200 mg to about650 mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg,about 350 mg to about 500 mg, about 400 mg to about 450 mg. Thesedosages may be administered once a day, twice daily, three times a day,or four times a day. In some embodiments the daily dose is administeredtwice daily (i.e. a 25 mg to 775 mg daily dose is administered as twodoses of 12.5 mg to 387.5 mg). In certain embodiments thetherapeutically effective amount of solabegron is 25 mg to 500 mg a daygiven in an immediate release formulation. In certain embodiments thetherapeutically effective amount of solabegron is 12.5 mg to 250 mg,given twice a day in an immediate release formulation.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein the therapeuticallyeffective amount of muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, is about 0.3 mg to about 90 mg. In certainembodiments, the therapeutically effective amount of the muscarinicreceptor antagonist is about 0.375 mg to about 0.75 mg, about 1 mg toabout 4 mg, about 4 mg to about 8 mg, about 5 mg to about 10 mg, about 5mg to about 30 mg, about 5 mg to about 85 mg, about 10 mg to about 80mg, about 15 mg to about 45 mg, about 15 mg to about 75 mg, about 20 mgto about 60 mg, about 20 mg to about 70 mg, about 25 mg to about 65 mg,about 30 mg to about 60 mg, about 35 mg to about 55 mg, about 40 mg toabout 50 mg. These dosages may be administered once a day, twice daily,three times a day, or four times a day.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein the sub-therapeuticallyeffective amount of muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, is any amount of the muscarinic receptor antagonistwhich is not therapeutically effective or is minimally therapeuticallyeffective alone, as was known in the art as of the date of the presentinvention, but which in combination with a therapeutically effectiveamount of solabegron, demonstrates a synergistic therapeutic effect.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effective amountof a muscarinic receptor antagonist or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof; wherein thevoided volume of the subject is increased, and wherein thetherapeutically effective amount of solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, is about 25 mg to about 775 mg and wherein thetherapeutically effective amount of muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, is about 0.3 mg to about 90 mg. In certainembodiments, the therapeutically effective amount of solabegron is about25 mg to about 500 mg, about 100 mg to about 750 mg, about 150 mg toabout 700 mg, about 200 mg to about 400 mg, about 200 mg to about 650mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg, about350 mg to about 500 mg, about 400 mg to about 450 mg. These dosages maybe administered once a day, twice daily, three times a day, or fourtimes a day. In some embodiments the daily dose is administered twicedaily (i.e. a 25 mg to 775 mg daily dose is administered as two doses of12.5 mg to 387.5 mg). In certain embodiments the therapeuticallyeffective amount of solabegron is 25 mg to 500 mg a day given in animmediate release formulation. In certain embodiments thetherapeutically effective amount of solabegron is 12.5 mg to 250 mg,given twice a day in an immediate release formulation. In certainembodiments, the therapeutically effective amount of the muscarinicreceptor antagonist is about 0.375 mg to about 0.75 mg, about 1 mg toabout 4 mg, about 4 mg to about 8 mg, about 5 mg to about 10 mg, about 5mg to about 30 mg, about 5 mg to about 85 mg, about 10 mg to about 80mg, about 15 mg to about 45 mg, about 15 mg to about 75 mg, about 20 mgto about 60 mg, about 20 mg to about 70 mg, about 25 mg to about 65 mg,about 30 mg to about 60 mg, about 35 mg to about 55 mg, about 40 mg toabout 50 mg. These dosages may be administered once a day, twice daily,three times a day, or four times a day.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof; wherein the voided volume of the subject isincreased; and wherein the therapeutically effective amount ofsolabegron about 25 mg to about 775 mg, and wherein thesub-therapeutically effective amount of muscarinic receptor antagonistor a pharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof; is any amount of the muscarinic receptor antagonistwhich is not therapeutically effective or is minimally therapeuticallyeffective alone, as was known in the art as of the date of the presentinvention, but which in combination with a therapeutically effectiveamount of solabegron, demonstrates a synergistic therapeutic effect. Incertain embodiments, the therapeutically effective amount of solabegronis about 25 mg to about 500 mg, about 100 mg to about 750 mg, about 150mg to about 700 mg, about 200 mg to about 400 mg, about 200 mg to about650 mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg,about 350 mg to about 500 mg, about 400 mg to about 450 mg. Thesedosages may be administered once a day, twice daily, three times a day,or four times a day. In some embodiments the daily dose is administeredtwice daily (i.e. a 25 mg to 775 mg daily dose is administered as twodoses of 12.5 mg to 387.5 mg). In certain embodiments thetherapeutically effective amount of solabegron is 25 mg to 500 mg a daygiven in an immediate release formulation. In certain embodiments thetherapeutically effective amount of solabegron is 12.5 mg to 250 mg,given twice a day in an immediate release formulation.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein the solabegron and themuscarinic receptor antagonist are co-administered.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein the solabegron and themuscarinic receptor antagonist are contained in a single dosage form,wherein the single dosage form is a pharmaceutical composition.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein the solabegron and themuscarinic receptor antagonist are administered separately.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased, and wherein there is a time delaybetween the administration of the solabegron and the muscarinic receptorantagonist.

In embodiments described herein, the method of treating overactivebladder in a subject in need thereof, comprises administering acombination comprising a therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein the voidedvolume of the subject is increased and one or more of the symptoms ofoveractive bladder is alleviated; wherein the one or more symptoms ofoveractive bladder is selected from the group consisting of urinaryurgency, frequency of micturitions, nocturia, and urgency urinaryincontinence, or a combination thereof.

The methods of the present invention may also be employed with othertherapeutic methods of treating one or more symptoms associated withoveractive bladder. Combination therapies according to the presentinvention thus include the administration of the beta-3 adrenergicreceptor agonist, e.g. solabegron, and the muscarinic receptorantagonist as well as optional use of other therapeutic agents includingother beta-3 adrenergic receptor agonists and/or muscarinic receptorantagonists. Such combination of agents may be administered together orseparately and, when administered separately this may occursimultaneously or sequentially in any order, both close and remote intime. The amounts of the compounds of the beta-3 adrenergic receptoragonist and the muscarinic receptor antagonist and the other optionalpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

Pharmaceutical Compositions

Solabegron

In some embodiments, a pharmaceutical composition for treatingoveractive bladder comprises solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative, or zwitterion thereof; andone or more pharmaceutically-acceptable carriers, diluents, orexcipients; wherein treating overactive bladder is measured by anincrease in voided volume.

In some embodiments the solabegron (Formula I) of the composition can beadministered as a salt, which can be anhydrous, hydrated, or solvatedwith a pharmaceutically-acceptable solvent such as ethanol. In aparticular embodiment, solabegron is administered as the hydrochloridesalt (Formula I-HCl). In a preferred embodiment, solabegronhydrochloride is the anhydrous hydrochloride salt.

The free base, and pharmaceutically-acceptable salts, for example, thehydrochloride salt, of solabegron can be prepared, for example,according to the procedures disclosed in International PatentApplication No. PCT/EP99/03958, filed Jun. 9, 1999, and published as WO99/65877 on Dec. 23, 1999; International Patent Application No.PCT/GB00/04697, filed Dec. 8, 2000 and published as WO 01/42195 on Jun.14, 2001; and International Patent Application No. PCT/US01/49355, filedDec. 17, 2001 and published as WO2006/113649 on Aug. 29, 2002.

In some embodiments, the solabegron of the composition can beadministered as a zwitterion (Formula I-ZW). In certain embodiments, thesolabegron zwitterion in the composition is a solid. In someembodiments, the solabegron zwitterion is amorphous. In furtherembodiments, the solabegron zwitterion in the composition is a crystal.In some embodiments, the solabegron zwitterion in the composition is asingle polymorph. In further embodiments, the solabegron zwitterion inthe composition is more than one polymorph. In further embodiments, thesolabegron zwitterion in the composition is a solid or crystallinehydrate of isopropanol solvate. In some embodiments, the solabegronzwitterion in the composition is characterized by a peak at 1552 cm-1upon infrared analysis. In further embodiments, the solabegronzwitterion in the composition is characterized by a peak at 184.6° C.upon differential scanning calorimetry analysis. In some embodiments,the solabegron zwitterion in the composition is characterized by anx-ray powder diffraction pattern having peaks expressed in degrees 2θ(±2) at 6.3, 12.6; 18.6; 18.9; 20.9; 22.4; 25.3; and 25.5. In someembodiments, the solabegron zwitterion in the composition ischaracterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 6.2, 12.5; 18.8; 20.6; and 25.2. In someembodiments, the solabegron zwitterion in the composition ischaracterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 6.2, 12.5; 18.6; 18.8; 20.6; 22.3, and25.2. In some embodiments, the solabegron zwitterion in the compositionis characterized by an x-ray powder diffraction pattern having peaksexpressed in degrees 2θ (±2) at 6.2, 12.5; 16.9, 18.6; 18.8; 20.6; 21.1,21.5; 22.3, 25.2; 26.6, and 32.9. In some embodiments, the solabegronzwitterion in the composition is characterized by an x-ray powderdiffraction pattern having peaks expressed in degrees 2θ (±2) at 17.6,18.7, 19.6, 20.1, 20.5, 23.7, and 25.8. In some embodiments, thesolabegron zwitterion in the composition is characterized by an x-raypowder diffraction pattern having peaks expressed in degrees 2θ (±2) at9.4, 15.1, 16.2, 17.6, 18.7, 19.6, 20.1, 20.5, 21.8, 22.6, 23.7, 24.8,25.8, and 28.9. In some embodiments, the solabegron zwitterion in thecomposition is characterized by an x-ray powder diffraction patternhaving peaks expressed in degrees 2θ (±2) at 6.1, 7.5, 9.4, 11.3, 14.5,15.1, 16.2, 17.6, 18.7, 19.6, 20.1, 20.5, 21.8, 22.6, 23.7, 24.8, 25.8,and 28.9. In further embodiments, the solabegron zwitterion in thecomposition is characterized by ¹H NMR peaks (¹H NMR, 300 MHz, DMSO-d₆)δ 8.15; 7.90; 7.70; 7.40; 7.30; 7.19; 6.82; 6.63; 6.00; 4.83; 3.30;2.95; and 2.82. In some embodiments, the solabegron zwitterion in thecomposition is characterized by ¹³C NMR of the peak (¹³NMR, 300 MHz,DMSO-d₆) δ 170.0; 148.0; 145.5; 140.3; 140.1; 135.4; 133.9; 130.0;129.6; 129.0; 128.3; 128.0; 127.3; 127.1; 125.7; 124.5; 114.8; 111.8;110.7; 62.8; 54.8; 44.6; 40.8; 40.0; 39.8; 39.4; 39.2; 38.8; 38.6; and25.4. In further embodiments, the solabegron zwitterion in thecomposition is at least about 98.0% by weight pure. In some embodiments,the solabegron zwitterion in the composition is at least about 98.0% byweight pure. In some embodiments, the solabegron zwitterion in thecomposition is at least about 99.0% by weight pure. In furtherembodiments, the solabegron zwitterion in the composition is at leastabout 99.5% by weigh pure. In some embodiments, solabegron zwitterion inthe composition is at least about 99.9% by weight pure. In furtherembodiments, the compound of solabegron zwitterion in the compositionhas no single impurity present in an amount greater than about 0.5% byweight. In some embodiments, the solabegron zwitterion in thecomposition has no single impurity present in an amount greater thanabout 0.25% by weight. In further embodiments, the solabegron zwitterionin the composition has no single impurity present in an amount greaterthan about 0.10% by weight.

In certain embodiments, the therapeutically effective amount ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof, may be asa daily dose or a single dose within a range of a lower limit ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof and anupper limit amount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof. In someembodiments the lower limit amount of solabegron is about 25 mg, about50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about, 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675mg, about 700 mg, about 725 mg, or about 750 mg. In some embodiments,the upper limit amount of solabegron is about 775 mg, about 750 mg,about 725 mg, about 700 mg, about 675 mg, about 650 mg, about 625 mg,about 600 mg, about 575 mg, about 550 mg, about 525 mg, about 500 mg,about 475 mg, about 450 mg, about 425 mg, about 400 mg, about 375 mg,about 350 mg, about 325 mg, about 300 mg, about 275 mg, about 250 mg,about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg,about 100 mg, about 75 mg, or about 50 mg. In some embodiments, thedaily dose may be any range between an upper and a lower limit of rangespreviously disclosed.

For example, the daily dose range may be about 25 mg to about 775 mg,about 50 mg to about 500 mg, about 100 mg to about 750 mg, about 150 mgto about 700 mg, about 200 mg to about 400 mg, about 200 mg to about 650mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg, about350 mg to about 500 mg, about 400 mg to about 450 mg of solabegron. Insome embodiments the daily dose is administered twice daily (i.e. a 25mg to 775 mg daily dose is administered as two doses of 12.5 mg to 387.5mg).

In certain embodiments the therapeutically effective amount ofsolabegron is 50 mg to 500 mg a day given in an immediate releaseformulation. In certain embodiments the therapeutically effective amountof solabegron is 25 mg to 250 mg, given twice a day in an immediaterelease formulation. In certain embodiments the therapeuticallyeffective amount is 100 mg to 200 mg, given twice a day in an immediaterelease formulation.

In some embodiments, a pharmaceutical composition for treatingoveractive bladder comprises solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative, or zwitterion thereof;wherein treating overactive bladder is measured by an increase in voidedvolume; and wherein the pharmaceutically-acceptable salt of thesolabegron is the hydrochloride salt.

In some embodiments, a pharmaceutical composition for treatingoveractive bladder comprises solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative, or zwitterion thereof;wherein treating overactive bladder is measured by an increase in voidedvolume; and wherein the solabegron is a zwitterion.

In some embodiments, a pharmaceutical composition for treatingoveractive bladder comprises solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative, or zwitterion thereof;wherein treating overactive bladder is measured by an increase in voidedvolume; and wherein the therapeutically effective amount of solabegronis about 25 mg to about 775 mg. In certain embodiments thetherapeutically effective amount of solabegron is about 50 mg to about500 mg, about 100 mg to about 750 mg, about 150 mg to about 700 mg,about 200 mg to about 400 mg, about 200 mg to about 650 mg, about 250 mgto about 600 mg, about 300 mg to about 550 mg, about 350 mg to about 500mg, about 400 mg to about 450 mg. is about 50 mg to about 800 mg. Incertain embodiments, the therapeutically effective amount of solabegronor a pharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, is about 100 mg to about 750 mg,about 150 mg to about 700 mg, about 200 mg to about 650 mg, about 250 mgto about 600 mg, about 300 mg to about 550 mg, about 350 mg to about 500mg, and about 400 mg to about 450 mg of compound. These dosages may beadministered once a day, twice daily, three times a day, or four times aday. In some embodiments the daily dose is administered twice daily(i.e. a 25 mg to 775 mg daily dose is administered as two doses of 12.5mg to 387.5 mg). In certain embodiments the therapeutically effectiveamount of solabegron is 50 mg to 500 mg a day given in an immediaterelease formulation. In certain embodiments the therapeuticallyeffective amount of solabegron is 25 mg to 250 mg, given twice a day inan immediate release formulation. In certain embodiments thetherapeutically effective amount is 100 mg to 200 mg, given twice a dayin an immediate release formulation.

Solabegron and a Muscarinic Receptor Antagonist

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist; wherein treating overactivebladder is measured by an increase in voided volume.

In some embodiments the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof,further comprises one or more pharmaceutically-acceptable carriers,diluents or excipients.

In some embodiments the muscarinic receptor antagonist further comprisesone or more pharmaceutically-acceptable carriers, diluents, orexcipients.

In some embodiments, solabegron is in the form of the hydrochloride salt(Formula I-HCl). In some embodiments, solabegron is a zwitterion(Formula I-ZW).

In some embodiments, the muscarinic receptor antagonist is selected fromoxybutynin, tolterodine, trospium, darifenacin, festerodine,hyoscyamine, propiverine, or solifenacin, or pharmaceutically-acceptablesalts thereof. In some embodiments the muscarinic receptor antagonist isselected from oxybutynin, tolterodine, or solifenacin, orpharmaceutically-acceptable salts thereof. In some embodiments,muscarinic receptor antagonist is oxybutynin, orpharmaceutically-acceptable salts thereof.

In certain embodiments, the therapeutically effective amount ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof, may be asa daily dose or a single dose within a range of a lower limit ofsolabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof and anupper limit amount of solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative or zwitterion thereof. In someembodiments the lower limit amount of solabegron is about 25 mg, about50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about, 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675mg, about 700 mg, about 725 mg, or about 750 mg. In some embodiments,the upper limit amount of solabegron is about 775 mg, about 750 mg,about 725 mg, about 700 mg, about 675 mg, about 650 mg, about 625 mg,about 600 mg, about 575 mg, about 550 mg, about 525 mg, about 500 mg,about 475 mg, about 450 mg, about 425 mg, about 400 mg, about 375 mg,about 350 mg, about 325 mg, about 300 mg, about 275 mg, about 250 mg,about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg,about 100 mg, about 75 mg, or about 50 mg. In some embodiments, thedaily dose may be any range between an upper and a lower limit of rangespreviously disclosed.

For example, the daily dose range may be about 25 mg to about 775 mg,about 25 mg to about 500 mg, about 100 mg to about 750 mg, about 150 mgto about 700 mg, about 200 mg to about 400 mg, about 200 mg to about 650mg, about 250 mg to about 600 mg, about 300 mg to about 550 mg, about350 mg to about 500 mg, about 400 mg to about 450 mg of solabegron. Insome embodiments the daily dose is administered twice daily (i.e. a 25mg to 775 mg daily dose is administered as two doses of 12.5 mg to 387.5mg).

In certain embodiments the therapeutically effective amount ofsolabegron is 25 mg to 500 mg a day given in an immediate releaseformulation. In certain embodiments the therapeutically effective amountof solabegron is 12.5 mg to 250 mg, given twice a day in an immediaterelease formulation.

In certain embodiments, the therapeutically effective amount of themuscarinic receptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof, may be as a daily doseor a single dose within a range of a lower limit of muscarinic receptorantagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof, and an upper limitamount of muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof. In some embodiments the lower limit amount of themuscarinic receptor antagonist is about 0.3 mg, about 0.75 mg, about 1mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,or about 85 mg. In some embodiments, the upper limit amount of themuscarinic receptor antagonist is about 90 mg, about 85 mg, about 80 mg,about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg,about 20 mg, about 15 mg, about 10 mg, about 5 mg, about 1 mg, or about0.75 mg. In some embodiments, the daily dose may be any range between anupper and a lower limit of ranges previously disclosed.

For example, the range may be about 0.375 mg to about 0.75 mg, about 1mg to about 4 mg, about 4 mg to about 8 mg, about 5 mg to about 10 mg,about 5 mg to about 30 mg, about 5 mg to about 85 mg, about 10 mg toabout 80 mg, about 15 mg to about 45 mg, about 15 mg to about 75 mg,about 20 mg to about 60 mg, about 20 mg to about 70 mg, about 25 mg toabout 65 mg, about 30 mg to about 60 mg, about 35 mg to about 55 mg,about 40 mg to about 50 mg of muscarinic receptor. These dosages may beadministered once a day, twice daily, three times a day, or four times aday.

In certain embodiments, the therapeutically effective amount of themuscarinic receptor antagonist amount is the therapeutically effectiveamount, as was known in the art as of the date of the present invention.

In one embodiment, a therapeutically effective amount of oxybutynin is,but is not limited to, about 5 mg to about 30 mg daily. In someembodiments, the therapeutically effective amount of oxybutynin is 5 mgtwo to four times a day in an immediate release formulation. In certainembodiments, the therapeutically effective amount of oxybutynin is about5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mgonce a day in an extended release formulation.

In one embodiment, a therapeutically effective amount of tolterodine is,but is not limited to, about 1 mg to about 4 mg daily. In someembodiments, the therapeutically effective amount of tolterodine isabout 1 mg to about 2 mg two times a day in an immediate releaseformulation. In some embodiments, the therapeutically effective amountof tolterodine is about 2 mg to about 4 mg once a day in an extendedrelease formulation.

In one embodiment, a therapeutically effective amount of trospium is,but is not limited to, about 20 mg to about 60 mg daily. In someembodiments, the therapeutically effective amount of trospium is about20 mg two times a day in an immediate release formulation. In someembodiments, the therapeutically effective amount of trospium is about60 mg once a day in an extended release formulation.

In one embodiment, a therapeutically effective amount of darifenacin is,but is not limited to, about 7.5 mg to about 15 mg daily. In someembodiments, the therapeutically effective amount of darifenacin isabout 7.5 mg to about 15 mg once a day

In one embodiment, a therapeutically effective amount of festerodine is,but is not limited to, about 4 mg to about 8 mg daily. In someembodiments, the therapeutically effective amount of festerodine is 4 mgto 8 mg once a day.

In one embodiment, a therapeutically effective amount of hyoscyamine is,but is not limited to, about 0.375 mg to about 0.75 mg daily.

In one embodiment, a therapeutically effective amount of propiverine is,but is not limited to, about 15 mg to about 45 mg daily of propiverinehydrochloride. In some embodiments, the therapeutically effective amountof propiverine is about 15 mg two to three times a day of propiverinehydrochloride.

In one embodiment, a therapeutically effective amount of solifenacin is,but is not limited to, about 5 mg to about 10 mg daily. In someembodiments, the therapeutically effective amount of solifenacin isabout 5 mg or about 10 mg once a day.

In certain embodiments the sub-therapeutically effective of themuscarinic receptor antagonist is any amount of the muscarinic receptorantagonist which is not therapeutically effective or is minimallytherapeutically effective alone, as was known in the art as of the dateof the present invention, but which in combination with atherapeutically effective amount of solabegron, demonstrates asynergistic therapeutic effect.

In some embodiments of the invention, the sub-therapeutically effectiveamount of the muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, may be as a daily dose or a single dose within arange of a lower limit of the sub-therapeutically effective amount ofmuscarinic receptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof and an upper limit amountof the sub-therapeutically effective amount of muscarinic receptorantagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof. In some embodiments thelower limit amount of the sub-therapeutically effective amount of themuscarinic receptor antagonist is about 0.1 mg, about 0.5 mg, about 1mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, or about 45 mg. In someembodiments, the upper limit amount of the sub-therapeutically effectiveamount of the muscarinic receptor antagonist is about 50 mg, about 45mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg,about 15 mg, about 10 mg, about 5 mg, or about 1 mg. In someembodiments, the daily dose may be any range between an upper and alower limit of ranges previously disclosed.

For example, the range may be about 0.1 mg to about 50 mg, about 1 mg toabout 45 mg, about 5 mg to about 40 mg, about 10 mg to about 35 mg,about 15 mg to about 30 mg, about 20 mg to about 25 mg, of thesub-therapeutically effective amount of muscarinic receptor antagonist.These dosages may be administered once a day, twice daily, three times aday, or four times a day.

In some embodiments of the invention, the muscarinic receptor antagonistcomprises a compound selected from the group consisting of oxybutynin,tolterodine, and solifenacin, or pharmaceutically-acceptable salts andpharmaceutically-acceptable derivatives thereof. In some embodiments,the muscarinic receptor antagonist comprises oxybutynin, in a totaldaily oral dose of about 1 mg to about 40 mg, preferably about 1 mg toabout 20 mg, more preferably about 2.5 mg to about 10 mg. In someembodiment, oxybutynin is administered in a total daily dose of 3.9 mgin a transdermal patch. In certain embodiments, oxybutynin isadministered transdermally as a gel which delivers 84 mg of oxybutynin.In another embodiment, the muscarinic receptor antagonist comprisestolterodine, in a total daily oral dose of about 1 mg to about 10 mg,preferably about 1 mg to about 8 mg, more preferably about 1 mg to about4 mg. In some embodiments, tolterodine is administered in a total dailydose of 4 mg. In certain embodiments, 2 mg of tolterodine isadministered twice a day. In still another embodiment, the muscarinicreceptor antagonist comprises solifenacin, in a total daily oral dose ofabout 1 mg to about 20 mg, preferably about 2.5 mg to about 15 mg, morepreferably about 2.5 mg to about 10 mg. In some embodiments, solifenacinis administered in a total daily dose of 5 mg. These drugs may beadministered once a day, twice daily, three times a day, or four times aday. In certain embodiments, the solabegron and the muscarinic receptorantagonist are co-administered. In some embodiments the solabegron andthe muscarinic receptor antagonist are contained in a single dosageform.

In some embodiments, the pharmaceutical compositions of the presentinvention are formulated to reduce desensitization of the beta-3adrenoceptor, particularly when compared to an immediate releaseformulation of solabegron that may be given, for example, twice daily.To prevent or reduce beta-3 adrenoceptor desensitization, thepharmaceutical compositions of solabegron or the pharmaceuticalcompositions comprising solabegron and an muscarinic receptor antagonistare formulated so that therapeutic administration occurs in a mannersuch that drug occupancy at the receptor occurs at levels that do notelicit significant receptor desensitization.

Thus in one embodiment, the present application describes apharmaceutical composition comprising a therapeutically effective amountof solabegron, wherein the pharmaceutical composition achieves a firsttarget C_(max), a second target C_(max), a first target C_(min) betweenthe first target C_(max) and the second target C_(max), and a secondtarget C_(min) after the second target C_(max). Further embodimentsdescribe pharmaceutical compositions, wherein said pharmaceuticalcomposition achieves a plasma concentration of about 1 μg/ml or less forabout 6 hours to about 9 hours during a twenty-four hour period. Furtherembodiments describe pharmaceutical compositions, wherein saidpharmaceutical composition achieves a target AUC of about 11,000 nghr/ml to about 30,000 ng hr/ml over a twenty-four hour period. Furtherembodiments describe pharmaceutical compositions, wherein the firsttarget C_(max) is achieved after the start of a first release ofsolabegron and the second target C_(max) is achieved after the start ofa second release of solabegron. Further embodiments describepharmaceutical compositions, wherein said first target C_(max) is about0.5 μg/ml to about 3.5 μg/ml. Further embodiments describepharmaceutical compositions, wherein said second target C_(max) is about1.5 μg·ml to about 4 μg/ml. Further embodiments describe pharmaceuticalcompositions, wherein said first C_(min) is about 0.25 μg/ml to about1.5 μg/ml. Further embodiments describe pharmaceutical compositions,wherein said second C_(min) is about 0.01 μg/ml to about 1.0 μg/ml.Further embodiments describe pharmaceutical compositions, wherein thetime between the first target C_(max) and the second target C_(max) isabout 2 to about 8 hours. Further embodiments describe pharmaceuticalcompositions, wherein the first C_(min) is achieved at about 4 to about8 hours after the first administration. Further embodiments describepharmaceutical compositions, wherein the second C_(min) is achievedbefore about 24 hours after administration of the pharmaceuticalcomposition. Further embodiments describe pharmaceutical compositions,wherein the first C_(max) is achieved at about 0.75 to about 4 hoursafter the first administration. Further embodiments describepharmaceutical compositions, wherein the second C_(max) is achieved atabout 2 to about 8 hours after the first C_(min). Further embodimentsdescribe pharmaceutical compositions, wherein the first releasecomprises about 75 mg to about 400 mg of solabegron. Further embodimentsdescribe pharmaceutical compositions, wherein the second releasecomprises about 100 mg to about 400 mg of solabegron. Furtherembodiments describe pharmaceutical compositions, further comprising oneor more muscarinic receptor antagonists as described herein.

In certain embodiments, the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof, andthe muscarinic receptor antagonist or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof, areco-administered. In some embodiments the solabegron and the muscarinicreceptor antagonist are contained in a single dosage form.

In certain embodiments the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative or zwitterion thereof, andthe muscarinic receptor antagonist or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof, areadministered separately. In some embodiments there is a time delaybetween the administration of the solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, and the muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof. In some embodiments, the time delay between theadministration of the beta-3 adrenergic receptor agonist and themuscarinic receptor antagonist is 5 minutes, 10 minutes, 15 minutes, 20minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.

One preferred pharmaceutical composition comprises solabegron, or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, tolterodine, or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof, and one or morepharmaceutically-acceptable carriers, diluents or excipients. Anotherpreferred pharmaceutical composition comprises solabegron, or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, oxybutynin, or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof, and one or morepharmaceutically-acceptable carriers, diluents or excipients. Anotherpreferred pharmaceutical composition comprises solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptable derivativeor zwitterion thereof, solifenacin, or a pharmaceutically-acceptablesalt, or pharmaceutically-acceptable derivative thereof, and one or morepharmaceutically-acceptable carriers, diluents or excipients.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, selected from the group consisting of oxybutynin,tolterodine, trospium, darifenacin, festerodine, hyoscyamine,propiverine, solifenacin, and pharmaceutically-acceptable salts thereof;wherein treating overactive bladder is measured by an increase in voidedvolume; and wherein the solabegron or a pharmaceutically-acceptablesalt, pharmaceutically-acceptable derivative, or zwitterion thereof,further comprises one or more pharmaceutically-acceptable carriers,diluents, or excipients.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof, selected from the group consisting of oxybutynin,tolterodine, trospium, darifenacin, festerodine, hyoscyamine,propiverine, and solifenacin, or pharmaceutically-acceptable salts orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume; andwherein the muscarinic receptor antagonist or apharmaceutically-acceptable salt, or pharmaceutically-acceptablederivative thereof, further comprises one or morepharmaceutically-acceptable carriers, diluents, or excipients.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof, selected from the group consisting of oxybutynin,tolterodine, trospium, darifenacin, festerodine, hyoscyamine,propiverine, and solifenacin, or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume, andwherein the solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and themuscarinic receptor antagonist or a pharmaceutically-acceptable salt, orpharmaceutically-acceptable derivative thereof; further comprises one ormore pharmaceutically-acceptable carriers, diluents, or excipients.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof, selected from the group consisting of oxybutynin,tolterodine, solifenacin, and pharmaceutically-acceptable salts thereof;wherein treating overactive bladder is measured by an increase in voidedvolume.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of oxybutynin; or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof, wherein treatingoveractive bladder is measured by an increase in voided volume.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount of ahydrochloride salt of solabegron, and a therapeutically effectiveamount, or a sub-therapeutically effective amount, of a muscarinicreceptor antagonist selected from the group consisting of oxybutynin,tolterodine, trospium, darifenacin, festerodine, hyoscyamine,propiverine, solifenacin, and or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount of azwitterion of solabegron, and a therapeutically effective amount, or asub-therapeutically effective amount, of a muscarinic receptorantagonist selected from the group consisting of oxybutynin,tolterodine, trospium, darifenacin, festerodine, hyoscyamine,propiverine, solifenacin, or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof, wherein treatingoveractive bladder is measured by an increase in voided volume.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist, selected from the groupconsisting of oxybutynin, tolterodine, trospium, darifenacin,festerodine, hyoscyamine, propiverine, and solifenacin, or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof wherein treating overactive bladder is measured by anincrease in voided volume; and wherein the solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof and the muscarinic receptor antagonistor a pharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof, are contained in a single dosage form.

In some embodiments, a pharmaceutical combination for treatingoveractive bladder comprises a therapeutically effective amount ofsolabegron, or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof; and atherapeutically effective amount, or a sub-therapeutically effectiveamount, of a muscarinic receptor antagonist or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof selected from the group consisting of oxybutynin,tolterodine, trospium, darifenacin, festerodine, hyoscyamine,propiverine, and solifenacin, or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof; wherein treatingoveractive bladder is measured by an increase in voided volume; andwherein the solabegron or a pharmaceutically-acceptable salt,pharmaceutically-acceptable derivative, or zwitterion thereof and themuscarinic receptor antagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof are contained in aseparate dosage forms.

While it is possible that, for use in medical therapy, the beta-3adrenergic receptor agonist, e.g. solabegron, or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof; muscarinic receptor antagonist, or apharmaceutically-acceptable salt or pharmaceutically-acceptablederivative thereof; may be administered as the chemical compound itself,the active ingredient or ingredients may also be administered formulatedas a pharmaceutical composition. Accordingly, the invention furtherprovides pharmaceutical compositions, which include therapeuticallyeffective amounts of the beta-3 adrenergic receptor agonist, solabegron,and therapeutically effective amounts, or sub-therapeutically effectiveamounts, of the muscarinic receptor antagonist, orpharmaceutically-acceptable salts thereof, and one or morepharmaceutically-acceptable carriers, diluents, or excipients. Thecarrier(s), diluent(s) or excipient(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation,capable of pharmaceutical formulation, and not deleterious to therecipient thereof. The invention also provides a process for thepreparation of a pharmaceutical formulation including admixing thebeta-3 adrenergic receptor agonist, solabegron, muscarinic receptorantagonist or pharmaceutically-acceptable salts thereof, with one ormore pharmaceutically-acceptable carriers, diluents or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose. Asis known to those skilled in the art, the amount of active ingredientper dose will depend on the condition being treated, the route ofadministration and the age, weight and condition of the patient, or thepharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Preferred unit dosage formulations are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Furthermore, such pharmaceutical formulations may be prepared by any ofthe methods well known in the pharmacy art.

Typically, the salts of the present invention arepharmaceutically-acceptable salts. Salts encompassed within the term“pharmaceutically-acceptable salts” refer to non-toxic salts of thecompounds of this invention. Salts of the compounds of the presentinvention may comprise acid addition salts derived from a nitrogen on asubstituent in a compound of the present invention. Representativepharmaceutically-acceptable salts include the following: acetate, acidphosphate, aluminum, amines, amino acids, ascorbate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, chloroprocaine,choline, citrate, N,N′-dibenzylethylenediamine, dicyclohexylamine,diethanolamine, dihydrochloride, edetate, edisylate, estolate, esylate,ethanesulfonate, ethylenediamine, formate, fumarate, gentisinate,glucaronate, gluceptate, gluconate, glutamate, glycollyl-arsanilate,hexyl-resorcinate, hydrabamine, hydrobromide, hydrochloride,hydroiodide, hydroxy-naphthoate, iodide, iron, isethionate,isonicotinate, lactate, lactobionate, laurate, lithium, magnesium,malate, maleate, mandelate, mesylate, methanesulfonate, methylbromide,methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate,nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, potassium,procaine, saccharate, salicylate, sodium, stearate, subacetate,succinate, sulfate, tannate, tartrate, teoclate, p-toluenesulfonate,tosylate, triethiodide, trimethylammonium, valerate, and zinc. Othersalts, which are not pharmaceutically-acceptable, may also be useful inthe preparation of compounds of the invention and form a further aspectof the invention.

The beta-3 adrenergic receptor agonist, e.g. solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, and the muscarinic receptorantagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof may be administered byany appropriate route. Suitable routes include oral, rectal, nasal, andparenteral (including intravesical, subcutaneous, intramuscular,intraveneous, transdermal, intradermal, intrathecal, and epidural).Administration can also be by means of a bladder pump or sustainedrelease in the bladder.

It will be appreciated that the preferred route may vary with, forexample, the condition of the recipient of the combination. It will alsobe appreciated that each of the agents administered may be administeredby the same or different routes and that the beta-3 adrenergic receptoragonist and muscarinic receptor antagonist may be compounded together ina pharmaceutical composition/formulation.

Further, the combinations and methods of the present invention cancomprise isotopes of solabegron and/or the muscarinic receptorantagonist, that is, the beta-3 adrenergic receptor agonists and/ormuscarinic receptor antagonists are isotopically labeled. In oneembodiment, the isotopically labeled compound has one or more hydrogenatoms replaced with either deuterium or tritium. In another embodiment,the isotopically labeled compound has one or more carbon atoms replacedwith ¹¹C, ¹³C or ¹⁴C. In one preferred embodiment the compositioncomprises deuterated solabegron.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically-acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be used ingranulating. The powder mixture can be run through a tablet machine, andif the result is imperfectly formed slugs, they can be broken intogranules, and the granules can be lubricated and incorporated back intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative toprevent sticking to the tablet forming dies by means of the addition ofstearic acid, a stearate salt, talc or mineral oil. The lubricatedmixture is then compressed into tablets. The compounds of the presentinvention can also be combined with free flowing inert carrier andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example, by coating or embedding particulatematerial in polymers, waxes or the like.

The agents for use according to the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

Agents for use according to the present invention may also be deliveredby the use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can include,without limitation, polyvinylpyrrolidone, pyran copolymer,poly-hydroxypropyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol or poly-ethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example, sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for example,water for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question; forexample, those suitable for oral administration may include flavoringagents.

In another embodiment, the pharmaceutical combination includes thebeta-3 adrenergic receptor agonist, e.g. solabegron or apharmaceutically-acceptable salt, pharmaceutically-acceptablederivative, or zwitterion thereof, and the muscarinic receptorantagonist or a pharmaceutically-acceptable salt orpharmaceutically-acceptable derivative thereof and optionally at leastone additional beta-3 adrenergic receptor agonist or muscarinic receptorantagonist. The muscarinic receptor antagonist is as described hereinabove.

Therapeutically effective amounts of the beta-3 adrenergic receptoragonist, solabegron, and therapeutically effective amounts, orsub-therapeutically effective amounts of the muscarinic receptorantagonist, and optionally additional beta-3 adrenergic receptor agonistor muscarinic receptor antagonist are administered to a mammal.Typically, the therapeutically effective amount of one of theadministered agents of the present invention will depend upon a numberof factors including, for example, the age and weight of the mammal, theprecise condition requiring treatment, the severity of the condition,the nature of the formulation, and the route of administration.Ultimately, the therapeutically effective amount will be at thediscretion of the attendant physician or veterinarian. Further, a lowerdose (sub-therapeutic dose) of the antimuscarinic agent can beadministered to provide superior efficacy of the combination whilecontrolling the side effects of the antimuscarinic agent.

The invention encompasses the treatment of any condition that issusceptible to agonism of the beta-3 adrenergic receptor, or antagonismof the muscarinic receptor, or a condition that is susceptible to bothagonism of the beta-3 adrenergic receptor, and antagonism of themuscarinic receptor.

Examples of conditions associated with over-activity of smooth musclewhich are suitable for treatment using a combination comprising thebeta-3 adrenergic receptor agonist and the muscarinic receptorantagonist of the present invention include OAB, gastrointestinalsyndromes such as irritable bowel syndrome (IBS), inflammatory boweldisease (IBD), ulcerative colitis, and the like. The pharmaceuticalcombination of the present invention may therefore be effective in thetreatment of such conditions. Beta-3 adrenergic receptors have also beenfound in cardiac tissue. The pharmaceutical combination of the presentinvention may therefore be effective in the treatment of cardiovasculardisease.

The following examples are intended to be illustrative of particularembodiments of the invention, and are not intended to limit the scope ofthe invention in any way.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety and the Journal of Biological Chemistry. Unless otherwise noted,all starting materials were obtained from commercial suppliers and usedwithout further purification. Specifically, the following abbreviationsmay be used in the examples and throughout the specification:

BID twice daily ECG Electrocardiogram g (grams) mg (milligrams) IRimmediate release L (liters) mL (milliliters) μL (microliters) mol(moles) M (molar) mM (millimolar) N (Normal) Kg (kilogram) mmol(millimoles) RT (room temperature) min (minutes) h (hours) QID fourtimes daily XL extended release

Example 1. Drug Interaction Study with Healthy Human Subjects

A drug interaction study was conducted in healthy human volunteers,using repeat oral doses of solabegron and oxybutynin administered singlyas well as in combination with each other, in order to assess theeffects on pharmacokinetic and pharmacodynamic parameters, as measuredby post void residual (PVR) volumes. PVR was measured in subjectstreated with each agent alone as well as in combination at steady-state.

The study was a two-cohort randomized, open label, repeat dose, 3-waycrossover study in healthy adult subjects. Two marketed formulations ofoxybutynin were used in the study: i) Ditropan IR®, which is immediaterelease (IR) oxybutynin; and ii) Ditropan XL® which is extended release(XL) oxybutynin. The total daily dose given was 20 mg. Solabegron wasadministered as tablets. Details of the solabegron tablet compositionused are provided in Table 1 (composition A).

The first cohort (n=14 subjects) was given solabegron 200 mg BID (100mg×2) alone for 5 days, this was followed in the second period byoxybutynin IR 5 mg QID alone for 5 days, and in the final dosing perioda combination of solabegron 200 mg BID (100 mg×2) with oxybutynin IR 5mg QID was administered for a period of 5 days.

A second cohort (n=12 subjects) was given solabegron 200 mg BID (100mg×2) alone for 5 days, this was followed in the second period byoxybutynin XL 10 mg BID alone for 5 days, and in the final dosing perioda combination of solabegron 200 mg BID (100 mg×2) with oxybutynin XL 10mg BID was administered for a 5 day period.

Each study session was separated by a washout period of at least 5 days.Safety assessments included vital signs, ambulatory blood pressuremonitoring (ABPM) physical examinations, clinical laboratory safetytests, 12-lead ECGs, PVR volume, to assess the potential for urinaryretention, and adverse events. PVR was also utilized as a biomarker ofbladder smooth muscle relaxation to determine if solabegron combinedwith oxybutynin had a greater effect on relaxation than either compoundalone in healthy subjects.

Finally, blood samples were collected for pharmacokinetic analysis ofplasma concentrations of, as appropriate: solabegron and its primaryactive metabolite as shown below; R-oxybutynin, S-oxybutynin and themetabolites R-desethyl oxybutynin and S-desethyl oxybutynin as shownbelow.

Primary active metabolite of solabegron,

Primary active metabolite of oxybutynin is desethyloxybutynin:

TABLE 1 Solabegron Tablet Composition A UNIT FORMULA COMPONENT (mg)FUNCTION Wet Granulation Ingredients (a) GW427353, B, ACTIVE 110* ActiveIngredient SUBSTANCE (b) MANNITOL 60   119.25 Filler (c)METHYLCELLULOSE, 10 Binder METHOCEL A15 PREMIUM LV (d) CROSCARMELLOSE 10Disintegrant SODIUM (e) POLOXAMER F 68   2.5 Surfactant Extra granularIngredients (f) CROSCARMELLOSE SODIUM  5 Disintegrant (g) MAGNESIUMSTEARATE   2.5 Lubricant (h) COLLOIDAL SILICON    0.75 Glidant DIOXIDETotal 250  *100 mg after correction for purity and salt/base conversion.

Composition A was prepared by the blending and wet granulation ofingredients (a) through (e), Table 1, in a suitable high shearmixer/granulator. Ingredients (f) through (h) were added to the driedgranulation, blended and compressed. Compressed tablets were coveredwith an aqueous film coat.

Results of the Drug Interaction Study—PVR Volume

Bladder ultrasound scans to measure PVR volumes were conducted on Day-1(one day prior to the dosing period) and Day 6 (sixth day of the dosingperiod) of each study session.

Subjects dosed with solabegron alone or oxybutynin IR alone showed amean increase from baseline of 4.4 mL and 45.7 mL in PVR volumerespectively, while subjects dosed with the combination of solabegronand oxybutynin IR unexpectedly showed a mean increase from baseline of79.8 mL. Subjects dosed with oxybutynin XL alone showed a mean increasefrom baseline of 20.2 mL in PVR volume while subjects dosed with thecombination of solabegron and oxybutynin XL unexpectedly showed a meanincrease from baseline of 50.8 mL in PVR volume. These data aresummarized in Table 2.

TABLE 2 PVR data Active ingredient(s) administered Mean increase frombaseline (mL) Solabegron 4.4 oxybutynin IR 45.7 oxybutynin XL 20.2solabegron and oxybutynin IR 79.8 solabegron and oxybutynin XL 50.8

These data indicate that in healthy subjects, solabegron given aloneshowed minimal changes in PVR volumes and oxybutynin IR or XL givenalone showed modest changes in PVR volume, but solabegron and eitheroxybutynin IR or oxybutynin XL given in combination showed greaterincreases in PVR volumes in each case than is expected from an additiveeffect of the two active ingredients. When oxybutynin IR is used as theantimuscarinic, the PVR of the combination treatment is 79.8 mL versus50.1 mL for the PVR sum of the individually administered drugs.Similarly, when oxybutynin XL is used as the antimuscarinic, the PVR ofthe combination treatment is 50.8 mL versus 24.6 mL for the PVR sum ofthe individually administered drugs. The latter comparison shows anincrease of over 100% for the combination treatment versus theindividual treatments.

This is interpreted as evidence of pharmacological synergism in thecombination treatment, which indicates increased efficacy in treatingone or more of the symptoms of OAB, since retaining more fluid in thePVR test indicates that the bladder muscles are more relaxed, therebyincreasing bladder capacity.

Example 2. Effects of the Combination of Beta-Adrenoceptor Agonists andAntimuscarinics on Bladder Contractility in Rats

Stimulation of efferent nerves to the urinary bladder results in therelease of acetylcholine (ACh) that stimulates post-junctionalmuscarinic (M3) receptors on urinary bladder smooth muscle, resulting incontraction and subsequent urination. M2 receptors are functionallyexpressed in human bladder smooth muscle and may also play a role inbladder contractility, however most likely indirectly by enhancing M3mediated contractions and inhibiting β-adrenoceptor mediated relaxation.Antimuscarinic drugs are believed to work primarily by blocking M3receptors, thus inhibiting the contractions associated with overactivebladder.

Another approach to treating overactive bladder involves targetingβ3-adrenoceptors, which are also located on urinary bladder smoothmuscle. The stimulation of post-junctional β3-adrenoceptors results inthe generation of cAMP and production of direct relaxation of bladdersmooth muscle.

In order to investigate a possible pharmacological synergy on thecombination of the muscarinic and the beta receptor pathways, thecombination of the muscarinic antagonist oxybutynin and the beta-3adrenoceptor agonist CL-316,243 (a very selective and potent rodentβ3-AR agonist) was tested on EFS (electrical field stimulation)-inducedresponses in urinary bladder strips from rats.

Longitudinal strips of rat detrusor muscle were suspended in organ bathchambers containing oxygenated Krebs solution (pH 7.4, gassed with 95%O₂ and 5% CO₂ at 37° C.). Prazosin (1 μM) was added to the Krebssolution in order to block al-adrenoceptors. Bladder responses weremeasured using isometric transducers and recorded using a dataacquisition system. Tissues were allowed to equilibrate under a restingtension of 1.0 g for 60 min. Following the equilibration period, stripswere exposed to KCl (80 mM) to measure their viability. Tissues werewashed and equilibrated for another 45 min period. Bladder strips werethen subjected to EFS using the following parameters: maximal current800 mA, frequency of 15 Hz, square pulse of 0.1 ms, trains of 4 s every2 min. After approximately 15 min (when EFS contractions hadstabilized), the selective β2-adrenoceptor antagonist ICI-118551 (30 nM)was incubated for 15 min. After stabilization of the contractileresponse, a concentration response curve was obtained for each bladderstrip by adding CL-316,243 or oxybutynin (1 nM to 10 μM) (orcorresponding vehicle) in log unit concentration increments.

In the first series of experiments it was determined that oxybutynin ata concentration of 10 nM produced a minimal contraction.

In a second series of experiments, a single concentration of oxybutyninat 10 nM (determined from the first series of experiments) was added toorgan bath chambers followed by various doses of CL-316,243 to provide aconcentration-response curve for CL-316,243.

In the presence of a minimally effective dose of oxybutynin, there wasan approximate 3.5-fold shift to the left of concentration-responsecurve to CL-316,243. The EC₅₀ for inhibiting bladder contraction byCL-316,243 was 7.2 nM; however, in the presence of oxybutynin (10 nM)the EC₅₀ was 2.1 nM.

In addition, maximal inhibition of EFS-induced contractions byCL-316,243 alone was 65%, however in the presence of oxybutynin (10 nM)inhibition by CL-316,243 achieved 80% inhibition.

The differences in the EC₅₀ values and the inhibition of the maximalresponse were statistically significant (p<0.05).

These data indicate there was significant pharmacological synergy of theefficacy of inhibiting bladder contraction with the combination of anantimuscarinic agent with a selective beta-3 adrenoceptor agonist.

Example 3. Effects of the Combinations of Various Beta-AdrenoceptorAgonists and Antimuscarinics on Rat Bladder Contractions Induced by EFS(Electrical Field Stimulation)

In this study various combinations of β3-adrenoceptor agonists andantimuscarinics were tested in isolated rat urinary bladder strips.

Urinary bladder smooth muscle strips were obtained from female rats(Sprague-Dawley strain, body weight 240-360 g). Two strips per bladderwere prepared and connected to tension transducers in 5 ml organ bathscontaining Krebs-Henseleit solution (kept at 37° C., pH 7.4, gassed with95% O₂/5% CO₂). Prazosin (1 μM) was added to the Krebs solution in orderto block al-adrenoceptors. Strips were equilibrated for at least 60 minat 1.0 g resting tension, during which tissues were washed every 15 min.Then, each strip was exposed to 80 mM KCl to verify its viability. Afteranother 45 min wash-out period, strips were subjected to EFS (electricalfield stimulation parameters: constant current 800 mA; frequency of 15Hz; square pulse of 0.1 ms, train of 4 s every 2 min). Afterstabilization, ICI-118,551 (30 nM), a β2-adrenoceptor antagonist, wasincubated for 15 min then 10 nM of oxybutynin, tolterodine, solifenacin,or their common solvent (vehicle control) were added to the strips foran additional 15 min. Cumulative concentrations of solabegron (10 nM-10μM), mirabegron (10 nM-10 μM) and CL-316,243 (1 nM-10 μM) were thenadded in half-log increments. At the end of CRC's, 10 μM forskolin (FSK)was added to determine maximal relaxation (FIG. 1).

Results are displayed in FIGS. 2-5, and are expressed as % inhibition(mean±SEM) of basal EFS-induced contractions (EFS values obtained 15 minafter addition of ICI-118,551).

Each CRC was fit using non-linear regression (GraphPad Prism® software)to obtain E_(max) and pIC₅₀ (−log IC₅₀) values. Mean CRCs for vehicleand treated strips were fit in parallel and statistically compared. Thefirst fit was used to compare E_(max) values and when these values werenot statistically different, a second fit was performed, sharingE_(max), in order to obtain pIC₅₀ values for each pair of curves.Differences were considered statistically significant when the nullhypothesis could be rejected at a risk a of less than 0.05.

As evidenced by the data presented in the Figures, the E_(max) values ofCL-316,243 were significantly increased in the presence of oxybutyninand tolterodine. Further, the IC₅₀ of CL-316,243 was significantlydecreased in the presence of oxybutynin.

For solabegron, the E_(max) values were significantly increased byoxybutynin, tolterodine and solifenacin. Further, the IC₅₀ values ofsolabegron were significantly lower in the presence of oxybutynin andtolterodine. For mirabegron, the E_(max) value appeared to be increasedin the presence of tolterodine. Further, the IC₅₀ values of mirabegronwere significantly lower in the presence of oxybutynin, tolterodine andsolifenacin.

Thus, it is clear that antimuscarinics can affect both the potency andefficacy of beta-3 adrenergic receptor agonists.

What is claimed is:
 1. A method of treating overactive bladder in ahuman in need thereof comprising orally administering to the human atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt thereof, wherein treating overactivebladder is treating an increase in urinary urgency.
 2. The method ofclaim 1, wherein treating an increase in urinary urgency is measured bya percent change from baseline in urinary urgency episodes.
 3. Themethod of claim 1, wherein treating an increase in urinary urgencyresults in a decrease in urinary urgency.
 4. The method of claim 1,wherein the solabegron or the pharmaceutically-acceptable salt thereofis in a pharmaceutical composition comprising one or morepharmaceutically-acceptable carriers, diluents, or excipients.
 5. Themethod of claim 4, wherein the pharmaceutical composition is selectedfrom a capsule, a tablet, a powder, a granule, a solution, a suspension,an edible foam, an edible whip, an oil-in-water liquid emulsion or awater-in-oil liquid emulsion.
 6. The method of claim 4, wherein thepharmaceutical composition is a tablet.
 7. The method of claim 1,wherein the pharmaceutically-acceptable salt is the hydrochloride salt.8. The method of claim 1 further comprising treating one or more ofsymptoms of overactive bladder selected from the group consisting ofmicturition frequency, nocturia, urinary incontinence, and a combinationthereof.
 9. A method of treating overactive bladder in a human in needthereof consisting of orally administering to the human atherapeutically effective amount of solabegron or apharmaceutically-acceptable salt thereof, wherein treating overactivebladder is treating an increase in urinary urgency.
 10. The method ofclaim 9, wherein treating an increase in urinary urgency is measured bya percent change from baseline in urinary urgency episodes.
 11. Themethod of claim 9, wherein treating an increase in urinary urgencyresults in a decrease in urinary urgency.
 12. The method of claim 9,wherein the solabegron or the pharmaceutically-acceptable salt thereofis in a pharmaceutical composition comprising one or morepharmaceutically-acceptable carriers, diluents, or excipients.
 13. Themethod of claim 12, wherein the pharmaceutical composition is selectedfrom a capsule, a tablet, a powder, a granule, a solution, a suspension,an edible foam, an edible whip, an oil-in-water liquid emulsion or awater-in-oil liquid emulsion.
 14. The method of claim 12, wherein thepharmaceutical composition is a tablet.
 15. The method of claim 9,wherein the pharmaceutically-acceptable salt is the hydrochloride salt.16. The method of claim 9 further comprising treating one or more ofsymptoms of overactive bladder selected from the group consisting ofmicturition frequency, nocturia, urinary incontinence, and a combinationthereof.